Lactotrophs are characterized by high basal activity, responsiveness to many compounds and capacity for proliferation. Their activity is inhibited by dopamine and stimulated by estradiol and several secretagogues. A dominant physiological prolactin releasing/regulating factor (PRF) has not emerged. Our research has brought forward a novel concept that the intermediate lobe of the posterior pituitary produces a substance with all the characteristics of a very potent physiological PRF. We propose that PRF is produced by a sub=-population of melanotrophs (PRF* cells) and stimulates prolactin gene expression, release and lactotroph proliferation. PRF* cells are subject to stimulation by opioid peptides and inhibition by prolactin and dopamine. We also postulate that the actions of estrogens that affect the lactotrophs are mediated, in part, via PRF* cells. Support for the role of the intermediate lobe in prolactin homeostasis comes from transgenic mice with strikingly large intermediate lobe tumors. These mice have hyperprolactinemia and their tumors exhibit marked PRF activity. The specific aims are: 1. To examine the cellular and endocrine properties of PRF* cells in the rat posterior pituitary, 2. To investigate the intermediate lobe as a target for estrogens. 3. To characterize PRF and prolactin release in transgenic mice with intermediate lobe tumors. This research will extend our knowledge of the regulation of prolactin homeostasis and will contribute to the diagnosis and management of clinical problems of pituitary adenomas, infertility and lactation.